European Molecular Biological Laboratory, DE-22607, Hamburg, Germany.
BIOSAXS GmbH, DE-22607, Hamburg, Germany.
Nat Commun. 2024 Sep 18;15(1):8175. doi: 10.1038/s41467-024-52478-0.
Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotrophic factor that is a disease-modifying drug candidate for Parkinson's disease. CDNF has pleiotropic protective effects on stressed cells, but its mechanism of action remains incompletely understood. Here, we use state-of-the-art advanced structural techniques to resolve the structural basis of CDNF interaction with GRP78, the master regulator of the unfolded protein response (UPR) pathway. Subsequent binding studies confirm the obtained structural model of the complex, eventually revealing the interaction site of CDNF and GRP78. Finally, mutating the key residues of CDNF mediating its interaction with GRP78 not only results in impaired binding of CDNF but also abolishes the neuroprotective activity of CDNF-derived peptides in mesencephalic neuron cultures. These results suggest that the molecular interaction with GRP78 mediates the neuroprotective actions of CDNF and provide a structural basis for development of next generation CDNF-based therapeutic compounds against neurodegenerative diseases.
脑多巴胺神经营养因子（CDNF）是一种非传统的神经营养因子，是帕金森病的一种疾病修饰药物候选物。CDNF 对应激细胞具有多种保护作用，但作用机制尚不完全清楚。在这里，我们使用最先进的高级结构技术来解析 CDNF 与 GRP78（未折叠蛋白反应 (UPR) 途径的主要调节剂）相互作用的结构基础。随后的结合研究证实了该复合物的结构模型，最终揭示了 CDNF 与 GRP78 的相互作用位点。最后，突变介导 CDNF 与 GRP78 相互作用的关键残基不仅导致 CDNF 结合受损，而且还消除了源自 CDNF 的肽在中脑神经元培养物中的神经保护活性。这些结果表明与 GRP78 的分子相互作用介导了 CDNF 的神经保护作用，并为开发针对神经退行性疾病的下一代基于 CDNF 的治疗化合物提供了结构基础。
